Process for preparing esters of 2-(6&#39;methoxy-2&#39;naphtyl)-propionic acid via rearrangement of new ketals of 2-halo-1-(6&#39;-methoxy-2&#39;-naphtyl)-propan-1-one and new esters of 2-(5&#39;-bromo-6&#39;-methoxy-2&#39;-naphtyl)-propionic acid thus prepared

ABSTRACT

Process for preparing esters of 2-(6&#39;-methoxy-2&#39;-naphtyl)-propionic acid via rearrangement of new ketals of 2-halo-1-(6&#39;-methoxy-2&#39;-naphtyl)-propan-1-one in the presence of a Lewis acid. 
     The esters thus obtained are useful as intermediate products for preparing Naproxen. 
     The process involves the preparation of the following new compounds: 
     ketals of 2-halo-1-(6&#39;-methoxy-2&#39;-naphtyl)-propan-1-one 
     esters of 2-(5&#39;-bromo-6&#39;-methoxy-2&#39;-naphtyl)-propionic acid 
     1-(5&#39;-bromo-6&#39;-methoxy-2&#39;-naphtyl)-propan-1-one 
     2-halo-(5&#39;-bromo-6&#39;-methoxy-2&#39;-naphtyl)-propan-1-one.

This invention relates to a new process for preparing esters of2-(6'-methoxy-2'-naphtyl)-propionic acid via rearrangement of new ketalsof 2-halo-1-(6'-methoxy-2'-naphtyl)-propan-1 one in the presence of aLewis acid; furthermore it relates to some new esters of2-(5'-bromo-6'-methoxy-2'-naphtyl)-propionic acid.

More particularly the new process of this invention is represented bythe following scheme: ##STR1## wherein R is selected from the groupcomprising an hydrogen and a halogen atom;

R' is selected from the group comprising an alkyl radical having from 1to 6 carbon atoms and a benzyl radical;

R" is selected from the group comprising an alkyl radical having from 1to 6 carbon atoms and a benzyl radical;

R' and R", together, are an alkylene radical having 2-6 carbon atomswhich, together with the ##STR2## group, forms an heterocyclic ring; Xis a halogen atom;

Y is selected from the group comprising an alkyl radical having from 1to 6 carbon atoms, a substituted alkyl radical having from 2 to 6 carbonatoms and a benzyl radical.

The esters of general formula II are useful as intermediate products forpreparing Naproxen (═D-2-(6'-methoxy-2'-naphtyl)-propionic acid) whichis widely used as a drug owing to its antiphlogistic, analgetic andantipyretic activity.

The most part of the known synthetic routes for preparing alphaaryl-alcanoic acids involves the substitution of the aromatic ring withan acyl radical because this substitution may be carried out in highyields and with a high positional selectivity. The subsequent step isconsisting in the transformation of the acyl moiety into the alkanoicmoiety via Darzen reaction, via a variation of Wittig reaction whichcomprises the use of methoxycarbenylides instead of carbenylides, viaGrignard reaction, via cyanidrine or via reduction to alcohol,subsequent halogenation and treatment with a cyanide or carbon monoxide.

All of the above mentioned procedures present many drawbacks becausethey involve many steps, the yields are usually low and the reagents areexpensive and highly polluting.

In consideration of what above, many efforts have been made to preparearyl-alkanoic acids via rearrangement of the acyl-derivatives.

A known oxidative rearrangement is the Willgerodt reaction, but it is ofindustrial value only for preparing the arylacetic acids from thearylmethyl-ketones and it does not allow to achieve good yields becauseof the many purifications that are needed for eliminating thesulfur-containing by-products.

British Pat. No. 1.535.690 describes a process which comprises (i) theacylation of an aromatic hydrocarbon (ii) the reaction of the ketonethus obtained to prepare the corresponding ketal (iii) the generation ofan enol ether from the corresponding ketal (iv) the rearrangement of theenol ether with thallium ions in an organic liquid containing, perequivalent of the enol ether at least one equivalent of a nucleophiliccompound. This process suffers the disadvantage that thallium can reactwith the aromatic moiety to form some by-products.

The alkanoic acids prepared according to this synthetic route containalways traces of thallium as metal and/or as metal-organic product andare potentially dangerous because of the very high toxycity of thallium.

Surprisingly, it has been now found that Lewis acids (J. March-AdvancedOrganic Chemistry, McGraw-Hill and Kogakusha e. 2 edt., 236-8; Chem.Rev., 75, No. 1, 1-20) act as catalysts in preparing esters of formulaII via rearrangement pathway of ketals of formula I.

In order to obtain the rearrangement, the process is carried out in sucha way that the catalyst exerts a good affinity toward the halogen atomand a poor affinity toward the oxygen atom of the ketal group in thealpha-halo-ketal (I).

Meantime, it must be avoided such a condition that catalyst acts as areducing agent and transforms alpha-halo-ketals (I) into ketals and/orketones.

Catalysts that may be used according to this invention are the organicsalts, such as acetate, propionate, benzoate, trifluoromethanesulphonate, methane sulphonate, etc. as well as the inorganic salts suchas chloride, bromide, iodide, sulphate etc. of Copper, Magnesium,Calcium, Zinc, Cadmium, Barium, Mercury, Tin, Antimony, Bismuth,Manganese, Iron, Cobalt, Nickel and Palladium.

A preferred embodiment of this invention contemplates the use of metalhalides such as ZnCl₂, CoCl₂, ZnBr₂, SnCl₂, FeCl₂, FeCl₃, NiBr₂, CdCl₂,MgCl₂, HgCl₂, Hg₂ Cl₂, SbCl₃, BaCl₂, CaCl₂, CuCl, CuCl₂, MnCl₂, SnCl₄,BiCl₃, PdCl₂.

The catalyst may be introduced directly into the reaction medium;alternatively, it is formed "in situ".

The catalyst is preferably used in catalytic amount; larger quantitiesdo not afford appreciable advantages.

The rearrangement according to this invention is preferably carried outin the presence of a suitable diluent. Examples of such diluents are thealiphatic halo-hydrocarbons, aliphatic cyclic-hydrocarbons, loweralcohols, aliphatic acids and their esters, aromatic hydrocarbons andaromatic halo-hydrocarbons such as dichloroethane, trichloroethane,chlorobenzene, toluene, methylene chloride, methanol, trimethylorthoformate, and their mixtures.

The rearrangement contemplated by this invention is conducted at atemperature in the range from about 0° C. to the reflux temperature ofthe diluent.

Considering that either ketals (I) or esters (II) are stable at hightemperature, a preferred embodiment of this invention contemplates theuse of high boiling diluents.

The reaction time differs according to the ketal reactivity, thecatalyst activity and the reaction temperature; so it is very wide andit is comprised in the range from about 1/2 hour to about 160 hours.

The meaning of Y in the general formula II is related to the nature ofthe ketal and/or the diluent.

When R' and R" are an alkyl radical or benzyl radicals and the diluentis not a nucleophilic compound, Y has the same meaning of R' and R".

When an alcohol is used as diluent it may also take part in theesterification and/or transesterification step by forming esters ofgeneral formula II wherein Y is the alkyl radical of the alcohol used asdiluent. When an alkylene-alpha-halo-ketal (I) is rearranged, then Y (inthe ester II) means an halo-alkyl-radical because the halogen atom (X informula I) replaces one hydroxyl-group or glycol used as precursorwhereas the other hydroxyl-group takes part in the formation of theester group.

Furthermore, scrambling between the anion of the metal salt and thehalogen-atom (X in formula I) may take place during the rearrangementstep so that the anion of the metal salt may be present as substituentinstead of X in the radical Y.

The new halo-ketals (I) are prepared in an easy way and in high yieldsfrom the corresponding ketones either (i) by halogenation of the ketoneand subsequent ketalization of the thus obtained alpha-halo-ketone or(ii) by ketalization of the ketone and subsequent halogenation of thethus obtained ketal.

The ketalization step may be carried out according to conventionalprocedures by means of an alcohol in the presence of an acid catalystand of an ortho ester.

When the ketal is prepared from a glycol, the water which is formedduring the reaction is usually removed by azeotropic distillation, forexample with benzene, toluene, xylene, trichloroethane, etc.

The introduction of the halogen-atom in alpha position of carbonyl groupor of ketal group may be carried out by means of conventional reagentssuch as sulfuryl chloride, cupric chloride, cupric bromide,N-bromo-succinamide, pyridine or pyrrolidone-perbromide hydrobromide.

The esters of formula II wherein R is a halogen atom are new,consequently they are a further object of this invention.

The halogenation step, the ketalization step and the rearrangement ofalpha-halo-ketals of general formula I can be carried out in the samereaction vessel without isolating any intermediate product and in thepresence of the same diluent.

The ketones that are used as starting material according to thisinvention may be prepared by acylating 2-methoxy-naphtalene or1-halo-2-methoxy-naphtalene according to the Friedel-Crafts reaction.

In addition 2-halo-1-(5'-bromo-6'-methoxy-2'-naphtyl)-propan-1-one maybe prepared via conventional bromination of6-methoxy-2-propionyl-naphtalene or of2-halo-1-(6'-methoxy-2'-naphtyl)-propan-1-one.

1-(5'-bromo-6'-methoxy-2'-naphtyl)-propan-1-one and2-halo-(5'-bromo-6'-methoxy-2'-naphtyl)-propan-1-one are new productsand therefor they are a further object of this invention.

The removal of the bromine atom from 5-position of the naphtalene ringis carried out according to conventional procedures such as catalytichydrogenation or reduction by means of Zinc and acetic acid or Zinc andformic acid.

The following specific description is given to enable those skilled inthis art to more clearly understand and practice the present invention.It should not be considered as a limitation upon the scope of theinvention but merely as being illustrative and representative thereof.

For all of the examples I.R. spectra have been recorded in nujol/NaCl;whereas N.M.R. spectra have been recorded with a 60 MHz spectrometer.The chemical shifts have been expressed in delta [ppm].

EXAMPLE 1 (a) 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane(A)

A mixture of 2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (257 g,0.877 mol) (prepared according to Bull. Soc. Chim. Fr., 1962, 90),trimethyl orthoformate (271.5 g, 2.56 mol), methanesulfonic acid (1.7 g)and of methanol (700 ml) is kept, under stirring, at 45° C. for 24 h.The reaction mixture is poured, under vigorous stirring, into asaturated sodium carbonate solution and extracted with ethyl ether(2×500 ml).

The combined organic extract is washed with a 2% sodium hydrogencarbonate solution.

Evaporation of the solvent in vacuo leaves2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane (290 g, 0.855mol, yield: 97.5%).

An analytically pure sample is prepared by crystallization from amethanol/trimethyl orthoformate mixture; m.p. 87°-89° C.

I.R.: C═O stretching is absent. No band is present in the 2.5-3.2microns region.

N.M.R.: (CDCl₃ /TMS): 1.53 (d, 3H, J=7 Hz); 3.26 (s, 3H); 3.43 (s, 3H);3.90 (s, 3H); 4.50 (q, 1H, J=7 Hz), 7-7.98 (m, 6H).

(b) 2-chloro-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane (B)

A mixture of CuCl₂.2H₂ O (24.56 g, 0.144 mol), lithium chloride (3.06 g,0.072 mol), 1-(6'-methoxy-2'-naphtyl)-propan-1-one (12.9 g, 0.060 mol)(prepared according to J. Chem. Soc. (C), 1966, 181) and of DMF (40 ml)is kept, under stirring, at 80° C. for 5 h.

The solution is poured into a 3% hydrochloric acid, extracted withethylether (2×100 ml). The combined organic extract is washed withwater, dried on Na₂ SO₄ and the solvent is removed in vacuo. The residueis crystallized from ethanol to give the chloroketone (10.1 g, 0.41 mol,yield: 68%) as analytically pure product, m.p. 76°-78° C.

I.R.: 1680 cm⁻¹ (C═O stretching).

N.M.R.: (CDCl₃ /TMS): 1.72 (d, 3H, J=7 Hz); 3.84 (s, 3H); 5.35 (q, 1H,J=7 Hz); 6.9-8.5 (m, 6H).

A mixture of 2-chloro-1-(6'-methoxy-2'-naphtyl)-propan-1-one (6 g, 24.1mmol), trimethyl orthoformate (8 g, 75.4 mmol), methanesulfonic acid(0.5 ml, 7.7 mmol) and of methanol (18 ml) is heated at reflux for 30 h.The reaction mixture is cooled to room temperature. The white solidwhich precipitates is collected by filtration, washed with a mixture oftrimethyl orthoformate and methanol and dried; 5.35 g, 18 mmol, yield:75%; m.p. 92°-94° C.

I.R.: C═O stretching is absent. No band is present in the 2.5-3.2microns region.

N.M.R.: (CH₂ Cl₂ /TMS): 1.42 (d, 3H, J=7 Hz); 3.3 (s, 3H); 3.45 (s, 3H);3.95 (s, 3H); 6.85-8.35 (m, 6H).

(c) 2-bromo-1,1-diethoxy-1-(6'-methoxy-2'-naphtyl)-propane (C)

A solution of 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane(obtained according to Example 1a) (3.39 g, 10 mmol), triethylorthoformate (1.34 g, 9 mmol) and of methansulfonic acid (0.098 g, 1mmol) in ethanol (30 ml) is kept at 46° C. for 2 h.

The reaction mixture is poured, under vigorous stirring, into asaturated sodium carbonate solution and extracted with ethyl ether(2×250 ml). The combined organic extract is washed with a 2% sodiumhydrogen carbonate solution and dried on Na₂ CO₃.

Evaporation of the solvent in vacuo leaves2-bromo-1,1-diethoxy-1-(6'-methoxy-2'-naphtyl)-propane (3.67 g, 10 mmol,yield: 100%) as oil.

I.R.: C═O stretching is absent. No band is present in the 2.5-3.2microns region.

N.M.R.: (CCl₄ /TMS): 1.23 (t, 6H, J=7 Hz); 1.53 (d, 3H, J=7 Hz); 3.43(q, 4H, J=7 Hz); 3.90 (s, 3H); 4.50 (q, 1H, J=7 Hz); 7.00-8.00 (m, 6H).

(d) 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphtyl)-1,3-dioxolane (D)

A mixture of 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)propane (1g, 2.94 mmol) (obtained according to Example 1a), trimethyl orthoformate(0.5 ml, 4.7 mmol), BF₃.Et₂ O (0.3 ml), and of ethylene glycol (10 ml,180 mmol) is kept at 50° C. for 3 h. It is cooled to room temperatureand poured, under vigorous stirring, into a saturated sodium carbonatesolution and extracted with ethyl ether (2×250 ml).

The combined organic extract is washed with a 2% sodium hydrogencarbonate solution.

Evaporation of the solvent in vacuo leaves2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphtyl)-1,3-dioxolane (0.97 g, 2.82mmol, yield: 98%).

An analytically pure product is obtained by crystallization frommethanol, m.p. 75° C.

I.R.: C═O stretching is absent. No band is present in the 2.5-3.2microns region.

N.M.R.: (CDCl₃ /TMS): 1.60 (d, 3H, J=7 Hz); 3.90 (s, 3H); 3.90 (m, 2H);4.13 (m, 2H); 4.48 (q, 1H, J=7 Hz); 7.04-7.92 (m, 6H).

(e) 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphtyl)-1,3-dioxane (E)

2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (10 g, 34 mmol),1,3-propandiol (10.5 g, 138 mmol), para-toluenesulfonic acid hydrate (1g, 5.3 mmol) and benzene (50 ml) are refluxed and stirred together for 1h in a flask beneath a Dean-Stark trap.

The reaction mixture is added dropwise to a well stirred saturatedsodium carbonate solution (100 ml), extracted with benzene (2×100 ml).The combined organic solution is washed with a 2% sodium hydrogencarbonate solution, dried (Na₂ CO₃), filtered and concentrated in vacuoto give 2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphtyl)-1,3-dioxane (11.9 g,34 mmol, yield: 100%) as oil.

I.R.: C═O stretching is absent. No band is present in the 2.5-3.2microns region.

N.M.R.: (CH₂ Cl₂ /TMS): 1.20 (m, 2H); 1.68 (d, 3H, J=7 Hz); 3.90 (m,4H); 3.96 (s, 3H); 4.30 (q, 1H, J=7 Hz); 7.12-7.98 (m, 6H).

(f)2-(1'-bromoethyl)-2-(6'-methoxy-2'-naphtyl)-4,5-dimethyl-1,3-dioxolane(F)

The preparation is carried out according to the method described inExample 1e.

Reagents: (∓)-2,3-butanediol (10 g, 111 mmol),2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (10 g, 34 mmol)

Catalyst: para-toluenesulfonic acid hydrate (1 g, 5.25 mmol)

Solvent: benzene (50 ml)

Reaction time: 7 h

Yield: 12.3 g, 33.7 mmol, 99%, as oil

I.R.: C═O stretching is absent. No band in the 2.5-3.2 microns region.

N.M.R. (CDCl₃ /TMS): 1.23 (m, 6H); 1.53 (broad d, 3H, J=7 Hz); 3.65 (m,2H); 3.83 (s, 3H); 4.43 (q, 1H, J=7 Hz); 7.00-8.00 (m, 6H).

(g) 2-(1'-bromo-ethyl)-2-(5'-bromo-6'-methoxy-2'-naphtyl)-1,3-dioxolane(G)

Bromine (7.9 g, 100 mmol) is added, in 30 minutes, to a stirred solutionof 2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (29.3 g, 100 mmol) inchloroform (200 ml), kept at room temperature. The precipitate isfiltered and heated at reflux with methanol. The heterogeneous mixtureis cooled to room temperature, the insoluble is filtered, washed withmethanol and dried:2-bromo-1-(5'-bromo-6'-methoxy-2'-naphtyl)-propan-1-one (24 g, 64.3mmol; yield: 64%); m.p. 168°-170° C.

I.R.: 1680 cm⁻¹ (C═O stretching).

N.M.R.: (CDCl₃ /TMS): 1.95 (d, 3H, J=7 Hz); 4.08 (s, 3H); 5.43 (q, 1H,J=7 Hz); 7.23-8.60 (m, 5H).

The 2-bromo-1-(5'-bromo-6'-methoxy-2'-naphtyl)-propan-1-one is convertedinto 2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphtyl)-1,3-dioxolaneaccording to the method described in example 1e.

Reagents: ethylene glycol (33.3 g, 0.54 mol),2-bromo-1-(5'-bromo-6'-methoxy-2'-naphtyl)-propan-1-one (20 g, 0.054mol)

Catalyst: paratoluenesulfonic acid hydrate (1 g, 5.3 mmol)

Solvent: toluene (25 ml)

Reaction time: 8 h

Yield: 22.1 g, 53 mmol, 99%; m.p. 103°-104° C. (methanol)

I.R.: C═O stretching is absent. No band is present in the 2.5-3.2microns region.

N.M.R.: (CDCl₃ /TMS): 1.60 (d, 3H, J=7 Hz); 4.00 (m, 2H); 4.03 (s, 3H);4.16 (m, 2H); 4.46 (q, 1H, 7 Hz); 7.20-8.36 (m, 5H).

EXAMPLE 2 dl-2-(6'-methoxy-2'-naphtyl)-propionic acid

(a) A mixture of 2-bromo-1-(6'-methoxy-2'-naphtyl)propan-1-one (5.86 g,20 mmol), trimethyl orthoformate (6 ml), methanesulfonic acid (0.2 ml,3.1 mmol) and methanol (16 ml) is refluxed under stirring until theketone is completely transformed into2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane.

To the solution thus obtained red cuprous oxide (1.44 g, 10 mmol) isadded; the reaction mixture is refluxed under stirring for 24 h.

The suspension is cooled to room temperature and poured into water, theresulting suspension is acidified with hydrochloric acid and extractedwith methylene chloride. The organic layer is separated and the solventis removed under reduced pressure; the residue is dissolved in methanolcontaining 30% sodium hydroxide aqueous solution. This solution isheated at reflux for 2 hours cooled to room temperature, poured intowater and extracted with methylene chloride. The aqueous layer isacidified with diluted hydrochloric acid and extracted with methylenechloride.

The organic extracts are collected and dried over anhydrous sodiumsulphate, then the solvent is removed under reduced pressure to give3.95 g of dl-2-(6'-methoxy-2'-naphtyl)-propionic acid melting at158°-160° C.

Yield: 86% of the theoretical amount as to the bromo-ketone used asstarting product.

(b) A mixture of 2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (5.86 g,20 mmol); trimethyl orthoformate (6 ml), p-toluene-sulfonic acid hydrate(0.19 g, 1 mmol) and methanol (16 ml) is refluxed under stirring untilthe transformation into2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane is complete.

To the solution thus obtained red cuprous oxide (0.4 g, 2.8 mmol) isadded; the thus obtained mixture is refluxed under stirring for 80 h.

By working up the reaction mixture according to the procedure disclosedin the Example 2a dl-2-(6'-methoxy-2'-naphtyl)-propionic acid (3.6 g) isobtained.

Yield 78% of the theoretical amount as to the bromo-ketone used asstarting material.

(c) A mixture of 2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane(20 mmol), cuprous bromide (10 mmol), trimethyl orthoformate (4 ml) andmethanol (16 ml) is refluxed under stirring for 160 h.

By following the procedure disclosed in the Example 2adl-2-(6'-methoxy-2'-naphtyl)-propionic acid is obtained whereas thecuprous salt is recovered quantitatively and it is suitable for beingrecycled.

Yield, 70% of the theoretical amount as to the bromo-ketone used asstarting material.

(d) A mixture of 2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (2.93 g,10 mmol), trimethyl orthoformate (3 ml), methanesulfonic acid (0.1 ml;1.35 mmol) and methanol (8 ml) is refluxed under stirring until thetransformation into2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane is complete.

To the solution thus obtained cupric benzoate (3.3 g, 11 mmol) andcopper powder (0.7 g, 11 mmol) are added; the thus obtained mixture isrefluxed under stirring for 20 h.

By working up the reaction mixture according to the procedure disclosedin the Example 2a dl-2-(6'-methoxy-2'-naphtyl)-propionic acid (0.95 g,4.1 mmol) is obtained.

Yield, 41% of the theoretical amount as to the bromo-ketone used asstarting material.

Analogous results have been obtained by using catalytic amounts of thecatalyst.

(e) A mixture of anhydrous cupric acetate (0.9 g, 5 mmol), copper powder(0.32 g, 5 mmol), methanesulfonic acid (0.7 mmol) and acetic anhydride(5 ml) is stirred for 1 h at 65° C.

To the mixture cooled to room temperature2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane (1.7 g, 5 mmol)is added.

The thus obtained mixture is heated to 65° C. and maintained at thistemperature, under stirring. for 20 h.

By working up the reaction mixture according to the procedure disclosedin the Example 2a dl-2-(6'-methoxy-2'-naphtyl)-propionic acid (0.67 g)is obtained.

Yield, 58% of the theoretical amount as to the bromo-ketone used asstarting material.

Analogous results have been obtained by using catalytic amounts of thecatalyst.

(f) A mixture of 2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (5.86 g,20 mmol), trimethyl orthoformate (6 ml), 96% sulfuric acid (0.51 ml, 5mmol) and of methanol (20 ml) is refluxed under stirring until thetransformation into2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane is complete.

To the solution thus obtained red cuprous oxide (2.88 g, 20 mmol) isadded; the thus obtained mixture is then refluxed under stirring for 16h.

By working up the reaction mixture according to the procedure disclosedin the Example 2a dl-2-(6'-methoxy-2'-naphtyl)-propionic acid (3.85 g)is obtained.

Yield, 84% of the theoretical amount as to the bromo-ketone.

Analogous results have been obtained by using catalytic amounts of thecatalyst.

(g) A mixture of 2-bromo-1-(6'-methoxy-2'-naphtyl)-propan-1-one (2.93 g,10 mmol), triethyl orthoformate (2 ml), methanesulfonic acid (0.2 ml,2.7 mmol) and of ethanol (8 ml) is refluxed, under stirring, for 48 h.

The solution of the ethyl-ketal thus obtained is cooled to 65° C. andred cuprous oxide (2.88 g, 20 mmol) added; the reaction mixture is thenkept at 65° C. under stirring for 8 h.

By working up the reaction mixture according to the procedure disclosedin the Example 2a dl 2-(6'-methoxy-2'-naphtyl)propionic acid (0.2 g,0.87 mmol) is obtained.

Yield 87% of the theoretical amount as to the bromo-ketone.

Analogous results have been obtained by using catalytic amounts of thecatalyst.

(h) A mixture of copper powder (0.65 g, 10.2 mmol), methanesulfonic acid(0.04 ml, 0.6 mmol), trimethyl orthoformate (1 ml) and of methanol (4ml) is heated at reflux, under nitrogen, for 30 minutes.

2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propionic acid (1.7 g, 5mmol) is added to the reaction mixture, cooled to room temperature.

The reaction mixture is heated at reflux for 40 h, under stirring andunder nitrogen.

dl-2-(6'-methoxy-2'-naphtyl)-propionic acid (0.35 g, 1.5 mmol; yield30%) (m.p. 158°-160° C.) is isolated by working up the reaction mixtureas described in Example 2a.

EXAMPLE 3 Methyl dl-2-(6'-methoxy-2'-naphtyl)-propionate

A solution is prepared by adding2-bromo-1,1-dimethoxy-1-(6'-methoxy-2'-naphtyl)-propane (339 g, 1 mol)prepared according to the procedure disclosed in the Example 2a, to 1000ml of methylene chloride. To this solution ZnCl₂ (19.8 g, 0.17 mol) isadded under stirring, at 20° C.

The suspension is kept under stirring, at 20° C. for 10 h. Thesuspension is then washed with 10% hydrochloric acid (2×250 ml) and thesolvent is removed by distillation under reduced pressure. The yield ofthe methyl dl-2-(6'-methoxy-2'-naphtyl)-propionate is 215 g (yield,88%).

EXAMPLE 4 2-bromoethyl-ester of dl2-(5'-bromo-6'-methoxy-2'-naphtyl)-propionic acid

A mixture of2-(1'-bromoethyl)-2-(5'-bromo-6'-methoxy-2'-naphtyl)-1,3-dioxolane (2 g,4.8 mmol), ZnBr₂ (0.1 g, 0.45 mmol) and of toluene (5 ml) is heated atreflux for 5 h. The reaction mixture is cooled, poured into 3%hydrochloric acid (50 ml) and extracted with toluene (2×50 ml). Thecombined organic extract is washed with water, dried (Na₂ SO₄) andfiltered.

Evaporation of the solvent under reduced pressure gives 2-bromo-ethylester of 2-(5'-bromo-6'-methoxy-2'-naphtyl)-propionic acid (1.98 g, 4.75mmol; yield 98%).

An analytically pure sample is obtained by crystallization frommethanol; m.p. 78°-79° C.

I.R.: 1730 cm⁻¹ (C═O stretching absent).

N.M.R.: (CDCl₃ /TMS): 1.57 (d, 3H, J=7 Hz); 3.40 (t, 2H, J=7 Hz); 3.94(s, 3H); 3.94 (q, 1H, 7 Hz); 4.37 (t, 2H, J=6 Hz); 7.06-8.34 (m, 5H).

In an analogous manner several alpha-halo-ketals have been rearranged inthe presence of several catalysts, in several solvent and at differenttemperatures.

The results that have been obtained are summarized in the followingtable wherein:

the alpha-halo-ketals are indicated with the capital letter whichfollows their chemical names in Example 1;

the solvents are indicated as M (methanol), DCE (dichloroethane), MEC(methylene chloride), TMOF (trimethyl orthoformate), TOL (toluene), TCE(tetrachloroethane), CB (chlorobenzene);

yields as to the ketal used as starting material are based on thepropionic acid obtained via hydrolisis of crude esters.

                                      TABLE                                       __________________________________________________________________________    Catalyst  Ketal                                                                              Diluent   Reaction                                             (mmoles)  (mmoles)                                                                           (ml)      time (h)                                                                           T (C.°)                                                                    Yield                                       __________________________________________________________________________    BaCl.sub.2 (1.6)                                                                        D (5)                                                                              TCE (5)   5    145 95                                          BiCl.sub.3 (5)                                                                          A (5)                                                                              MEC (10)  24   15  35                                          CaCl.sub.2 (1.6)                                                                        D (5)                                                                              TCE (5)   24   145 15                                          CaCl.sub.2 (1.6)                                                                        D (5)                                                                              TCE (5)   7    145 95                                          CoCl.sub.2 (15)                                                                         A (5)                                                                              M (5) + TMOF (1)                                                                        120  60  45                                          CoCl.sub.2 (10)                                                                         A (10)                                                                             DCE (10)  72   80  40                                          CoCl.sub.2 (1.5)                                                                        D (4.5)                                                                            TOL (4)   10   110 98                                          CuCl.sub.2 (5)                                                                          A (5)                                                                              DCE (10)  24   60  10                                          CuCl.sub.2 (15)                                                                         A (5)                                                                              M (5) + TMOF (1)                                                                        120  60  30                                          FeCl.sub.2 (1.6)                                                                        D (5)                                                                              TOL (5)   10   110 80                                          FeCl.sub.3 (6)                                                                          A (6)                                                                              MEC (6)   14   15  78                                          FeCl.sub.3 (57)                                                                         A (57)                                                                             MEC (57)  5    0   77                                          Hg.sub.2 Cl.sub.2 (1.6)                                                                 D (5)                                                                              TCE (5)   6    145 92                                          HgCl.sub.2 (1.6)                                                                        D (5)                                                                              TOL (5)   3    110 87                                          MgCl.sub.2 (1.6)                                                                        D (5)                                                                              TCE (5)   22   145 35                                          MnCl.sub.2 (15)                                                                         A (5)                                                                              M (5) + TMOF (1)                                                                        120  60  30                                          NiBr.sub.2 (1.6)                                                                        D (5)                                                                              TCE (5)   21   145 28                                          PdCl.sub.2 (15)                                                                         A (5)                                                                              M (5) + TMOF (1)                                                                        3    60  92                                          SbCl.sub.3 (1.6)                                                                        D (5)                                                                              TCE (5)   3    145 96                                          SnCl.sub.2 (1.6)                                                                        D (5)                                                                              TOL (5)   12   110 95                                          SnCl.sub.4 (5)                                                                          A (5)                                                                              MEC (10)  24   20  20                                          ZnBr.sub.2 (3)                                                                          D (15)                                                                             TOL (30)  4    110 98                                          ZnBr.sub.2 (1.3)                                                                        D (5)                                                                              CB (5)    0.5  132 97                                          ZnBr.sub.2 (0.45)                                                                       G (4.8)                                                                            TOL (5)   5.5  110 98                                          ZnCl.sub.2 (22)                                                                         A (155)                                                                            MEC (150) 4    30  84                                          ZnCl.sub.2 (109)                                                                        A (750)                                                                            MEC (750) 12   20  86                                          ZnCl.sub.2 (5)                                                                          A (50)                                                                             MEC (50)  16   15  96                                          ZnCl.sub.2 (73)                                                                         A (500)                                                                            TOL (700) 6    60  80                                          ZnCl.sub.2 (170)                                                                        A (1000)                                                                           MEC (1000)                                                                              10   20  88                                          ZnCl.sub.2 (11)                                                                         B (10)                                                                             MEC (15)  8    45  13                                          ZnCl.sub.2 (2.5)                                                                        C (10)                                                                             MEC (17)  24   15  40                                          ZnCl.sub.2 (8.4)                                                                        D (68)                                                                             TOL (200) 6    110 96                                          ZnCl.sub.2 (3)                                                                          D (3)                                                                              MEC (6)   24   15  10                                          ZnCl.sub.2 (3)                                                                          E (9)                                                                              TOL (10)  16   90  90                                          ZnCl.sub.2 (4.5)                                                                        F (13.7)                                                                           TOL (15)  14   90  80                                          ZnCl.sub.2 (7)                                                                          F (7)                                                                              MEC (20)  24   45  30                                          ZnCl.sub.2 (1.6)                                                                        G (5)                                                                              TOL (5)   2    110 90                                          Zn (OAc).sub.2 (0.25)                                                                   D (5)                                                                              TOL (5)   2    110 98                                          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We claim:
 1. Process for preparing a compound having the formula:##STR3## wherein R is selected from the group consisting of a hydrogenand a bromine atom; andY is selected from the group consisting of analkyl radical having from 1 to 6 carbon atoms, a haloalkyl radicalhaving from 2 to 6 carbon atoms, and a benzyl radical;which comprisesthe rearrangement of a compound having the formula: ##STR4## wherein Rhas the above mentioned meaning; R' is selected from the groupconsisting of an alkyl radical having from 1 to 6 carbon atoms and abenzyl radical; R" is selected from the group consisting of an alkylradical having from 1 to 6 carbon atoms and a benzyl radical; or R' andR", together, are an alkylene radical having from 2-6 carbon atomswhich, together with the ##STR5## group, forms a heterocyclic ring; andX is a halogen atomin the presence of a catalytic amount of a Lewisacid.